Humam Kadara: An atlas of normal and cancerous epithelial cells in lung adenocarcinoma

Humam Kadara, Professor of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center, posted on LinkedIn:

“At last, at long last, our labor of love is out today in Nature! By generating an atlas of normal and cancerous epithelial cells in lung adenocarcinoma we unearth cellular states/subsets that underlie inception of the disease!

To study the landscape of epithelial cell states in lung adenocarcinoma pathogenesis, we performed scRNA-seq of epithelial cells from 63 tissues from 16 patients with the disease. We first analyzed tumor cells and found that those with KRAS mutations were quite different from all other tumor cells. KRAS mutant tumor cells distinctively exhibited a state of reduced alveolar identity/lineage.

What stood out in our analysis of “normal” cell populations is a subset of alveolar intermediate cells that had features of both alveolar type II (AT2) and type I (AT1) cells. We took a deep dive into alveolar intermediates and inferred that a subset with relatively high Krt8 expression (which we refer to here as KACs) was for the most part involved in one of two routes: AT2 to AT1 trans differentiation and development of tumor cells.

Interestingly, among alveolar cells, only KACs had KRAS mutations! Is it possible that these KACs are the sole harbingers of mutations in peripheral “normal” tissues in the lung and thus are culprits in tumor initiation? To dig deeper, we sought to study KACs in animal models of lung adenocarcinoma.

Excitingly, we found that while KACs were nearly absent in saline-treated controls, they were enriched in tobacco carcinogen-exposed lungs prior to development of tumors, and they persisted for months after carcinogen cessation! KACs in mice acquired KRAS mutations, were spatially located in close proximity to lung tumors, developed from AT2 cells post tobacco carcinogen, and were associated with development of lung tumor cells. Organoids of AT2 cells with KAC features c were very sensitive to KRAS p.G12D inhibitor MRTX1133! One could argue that targeting KRAS may be valuable for early therapy of KRAS mutant lung adenocarcinoma!

Lastly, using reporter mice, we found that lung tumors indeed developed from KACs suggesting that these alveolar intermediate cells are precursors for KRAS mutant lung tumors.

There are still many questions to answer on what controls the fate of alveolar intermediates vis-a-vis the intersection between injury repair mechanisms and lung tumorigenesis. We and others are exploring various mechanisms that impinge on transformation of KACs.

This work was collaboratively done with Linghua Wang at MD Anderson and Jichao Chen now University of Cincinnati and jointly led by two spectacular scientists Guangchun Han and Ansam Sinjab. Grateful for glorious efforts from Zahraa Rahal and Anne Lynch, members of my lab and the Wang, Chen labs, as well as from various groups from my institution MD Anderson Cancer Center and elsewhere. Grateful for funding from the NCI, CPRIT, Johnson and Johnson, and the Andrew Sabin Family Foundation that supported this work.”

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Source: Humam Kadara/LinkedIn